1. Field of the Invention
The present invention is directed to new cephem derivatives represented by the general formula ##STR4## in which the Acyl substituent is a group of the formula ##STR5## where Ar is an optionally substituted lipophilic phenyl, naphthyl or pyridyl group, R.sup.1 represents either the residue of a heterocyclic amino acid or a C.sub.2 -C.sub.10 alkyl group substituted by both a carboxyl or sulfonyl group and a group of the formula --NR.sup.9 R.sup.10 or ##STR6## in which R.sup.9 and R.sup.10 are each independently hydrogen or C.sub.1 -C.sub.6 alkyl, said C.sub.2 -C.sub.10 alkyl group being optionally interrupted by one or more nitrogen atoms or carbonyl groups, and R.sup.2 and R.sup.3 are each independently hydrogen, alkyl or aminoalkyl. The derivatives are gram-positive antibacterial agents, especially useful in the treatment of diseases caused by methicillin-resistant Staphylococcus aureus (also referred to below as MRSA or methicillin-resistant S. aureus).
2. Description of the Prior Art
The literature discloses a vast number of cephem derivatives having a wide variety of C-3 and C-7 substituents. Applicants are not aware, however, of any literature disclosing compounds with the combination of C-3 and C-7 substituents found by applicants to give good activity against MRSA organisms. There are, however, references which disclose cephalosporins having the type of 7-substituents or the type of 3-substituents present in the compounds claimed in the present application.
For example, there are references which disclose applicants' C-7 substituents. Among such references disclosing 7-substituents of the type ##STR7## where Ar is an aromatic group are the following:
U.S. Pat. No. 4,056,676 discloses cephem derivatives of the general formula ##STR8## where Z is hydrogen or fluorine; and when Z is hydrogen, each of X and Y is hydrogen or chlorine selected so that the phenyl ring is substituted with 1 or 2 chlorine atoms and so that when one chlorine atom is present said chlorine atom is in the 3-position, and when two chlorine atoms are present said chlorine atoms are in the 3,4-, the 3,5- or the 2,5-positions; and when Z is fluorine, said fluorine is in the 3- or 4-positions of the phenyl ring and each of X and Y is hydrogen or chlorine selected so that when the phenyl ring is substituted with 1 or 2 chlorine atoms, one of the chlorine atoms is in the 3- or 4-position of the phenyl ring; R.sup.1 is hydrogen, dicyclohexylamine, or a pharmaceutically acceptable cation; and R is, inter alia, N-pyridino. Among the compounds specifically disclosed are those of the formulae: ##STR9## The compounds disclosed are said to be useful for treating and inhibiting the growth of MRSA organisms.
The cephalosporin derivative of the formula ##STR10## is disclosed in Antimicrobial Agents and Chemotherapy--1966, pg. 573-580 at page 576 (Compound No. 48).
J. Antibiotics, 26(12), 737-744, 1973, discloses the compound of the formula ##STR11##
U.K. Patent 998,265 discloses cephem derivatives of the general formula ##STR12## in which R.sup.1, taken alone, is --OH, C.sub.1 -C.sub.8 acyloxy, or tertiaryamino, R.sup.2 is --OH when R.sup.1 is --OH, R.sup.2 is --OH when R.sup.1 is C.sub.1 -C.sub.8 acyloxy, R.sup.2 is --O-- when R.sup.1 is tertiaryamino, R.sup.1 and R.sup.2, when taken together, are --O--, R.sup.3 and R.sup.4 represent hydrogen, alkyl radicals having from 1 to 6 carbon atoms, alkenyl radicals having from 2 to 6 carbon atoms, cycloalkyl radicals having from 5 to 7 carbon atoms, or alkoxyalkyl radicals having from 2 to 6 carbon atoms; n represents 0 to 4; and R.sup.5 represents an alkyl radical having from 1 to 6 carbon atoms, an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, a cycloalkyl radical having 5 or 6 carbon atoms, phenyl, .beta.-furyl, .beta.-thienyl, thienyl, or naphthyl, or a fluoro, chloro, bromo, nitro, trifluoromethyl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkylmercapto, or C.sub.1 -C.sub.4 alkoxy substitution product of such radicals.
U.K. Published Application No. 2,007,221 A discloses cephalosporin derivatives of the formula ##STR13## wherein Y is hydrogen, chlorine, bromine, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; Z is a bond, oxygen or sulfur; W is hydrogen, methyl, amino, hydroxy, SO.sub.3 H or COOR.sub.4 wherein R.sub.4 is hydrogen or 5-indanyl with the proviso that when Z is oxygen or sulfur, W is other than hydroxy; R.sub.1 is hydrogen or methoxy; R.sub.2 is hydrogen, acetoxy, 1,3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio, 1,3,4-oxadiazol-2-ylthio, 5-methyl-1,3,4-oxadiazol-2-ylthio, 1,3,4-triazol-2-ylthio, 5-methyl-1,3,4-triazol-2-ylthio, 1,2,3-triazol-5-ylthio, pyridinium or 4-aminocarbonylpyridinium; R.sub.3 is hydrogen, a negative charge when R.sub.2 is pyridinium or 4-aminocarbonylpyridinium, a cation of an alkali metal or an alkaline earth metal, ammonium or organic ammonium cations, C.sub.1 -C.sub.4 alkyl, (C.sub.2 -C.sub.5 alkanoyloxy)methyl, (C.sub.2 -C.sub.5) alkanoylamino)methyl, [C.sub.2 -C.sub.5 alkanoyl(C.sub.1 -C.sub.4 alkoxy)carbonyl(C.sub.1 -C.sub.4 alkyl)-amino-methyl, p-(C.sub.2 -alkanoyloxy)benzylamino(C.sub.2 -C.sub.15 alkanoyloxy)methyl, (C.sub.1 -C.sub.4 alkyl)amino(C.sub.2 -C.sub.15 alkanoyloxy)methyl or di(C.sub.1 -C.sub.4 alkyl)amino(C.sub.2 -C.sub.15 alkanoyloxy)methyl; and pharmaceutically acceptable salts thereof.
U.S. Pat. No. 3,217,000 discloses cephem derivatives of the formula ##STR14## wherein Thi is 2-thienyl or 3-thienyl and R is a substituent at the 3 or 4 position of the pyridino ring selected from the group consisting of cyano, carboxy, carbamyl, N-methylcarbamyl, carbo(C.sub.1 -C.sub.4 alkoxy), hydroxy and (C.sub.1 -C.sub.4)alkanoyl; and the salts thereof with pharmaceutically acceptable acids.
There is also literature disclosing cephalosporins having 3-substituents of the type ##STR15## where R is an optionally substituted aliphatic or aromatic group. Among such references are those of the following:
U.S. Pat. No. 4,758,557 discloses cephalosporin derivatives of the general formula ##STR16## wherein A represents an alkanoyloxy group having 2-5 carbon atoms; a carbamoyloxy group; an azido group; or an unsubstituted or substituted pyridylthio group of the formula ##STR17## where n is 0 or an integer of 3-5; R.sup.1 and R.sup.2 may be the same or different and each represents a hydrogen atom, a halogen atom, a carboxyl group or an optionally halogen-substituted lower-alkyl group having 1-5 carbon atoms; or an unsubstituted or substituted pyridiniumthio group of the formula ##STR18## where n, R.sup.1 and R.sup.2 have the same meanings as above; R.sup.3 represents a linear or branched-chain alkyl group having 1-5 carbon atoms, a halogen-substituted alkyl group, a cyclopropyl group, a cyclopropylmethyl group, an alkenyl group, an oxygen atom or a group of (--CH.sub.2).sub.m --B where m is an integer of 0-3 and B represents a hydroxyl group, an alkoxy group, an amino group, an alkyl-substituted amino group, a carboxyl group, a carbamoyl group, a sulfonic acid group, a sulfonic acid amide group, a hydroxamic group, a cyano group, a thiol group, an alkylthio group, a methanesulfonylaminocarbonyl group or an acetamidosulfonyl group; or an unsubstituted or substituted pyridinium group of the formula ##STR19## where n has the same meaning as above; R.sup.4 and R.sup.5 may be the same or different and each represent a hydrogen atom, a linear or branched alkyl group having 1-5 carbon atoms, a carboxyl group, a carbamoyl group, a sulfonic acid group, a sulfonic acid amide group, a linear or branched alkylthio group having 1-5 carbon atoms, a halogen-substituted alkylthio group, a cycloalkanothio group, a carbamoylalkylthio group, an alkoxyalkylthio group or an alkyl-substituted aminoalkylthio group; or a 5- or 6-membered heterocyclicthio or bicycloheterocyclicthio group of the formula EQU --S--Het
wherein Het represents an optionally substituted thiazole, isothiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,3,4-tetrazole, pyrimidine, 1,2,4-triazine, benzothiazole, benzimidazole, benzoxazole, 1,3,4-triazaindolidine or 2,3-dihydro-1H-indolidinium group.
Illustrative of the compounds encompassed by U.S. Pat. No. 4,758,557 is MT0703 having the structure ##STR20## which is disclosed in J. Antibiotics 43(2), 189-198, 1990.
U.S. Pat. No. 4,786,633 discloses cephalosporin derivatives of the formula ##STR21## wherein R.sup.2 is a substituted or unsubstituted heterocyclic group having 1-3 hetero atoms selected from the group consisting of nitrogen and sulfur. The R.sup.2 group may be, for example, a group of the formula ##STR22## where R.sup.4 is lower alkenyl, lower alkyl, or a lower alkyl group substituted with a carbamoyl group and R.sup.5 and R.sup.6 are the same or different and each represent hydrogen or lower alkyl.
Published European Patent Application 409,164 A2 discloses cephalosporin derivatives of the formula ##STR23## wherein R.sup.1 is an amino group or acylamino; R.sup.2 is hydrogen or methoxy; R.sup.3 is hydrogen or a mono- or divalent substituent; R.sup.4 is optionally protected vic-dihydroxyaryl; R.sup.5 is straight or branched lower alkylene; R.sup.6 is hydrogen, a carboxy-protecting group or a negative charge when combined with Y; X is oxygen, sulfur, or sulfinyl; and Y is an anion or a negative charge when combined with R.sup.6 ; and the dotted line shows the presence or absence of a bond.